Identification of genetic loci that regulate susceptibility to disease has promised insight into pathophysiologic mechanisms and the development of novel therapies for common human diseases. Family studies clearly demonstrate a heritable predisposition to many common human diseases such as asthma, autism, schizophrenia, multiple sclerosis, systemic lupus erythematosus, and type I and type II diabetes mellitus. For a review, see Risch, Nature 405, 847-856, 2000. Over the last 20 years, causative genetic mutations for a number of highly penetrant, single gene (Mendelian) disorders such as cystic fibrosis, Huntington's disease and Duchene muscular dystrophy have been identified by linkage analysis and positional cloning in human populations. These successes have occurred in relatively rare disorders in which there is a strong association between the genetic composition of a genome of a species (genotype) and one or more physical characteristics exhibited by the species (phenotype).
It was hoped that the same methods could be used to identify genetic variants associated with susceptibility to common diseases in the general population. For a review, see Lander and Schork, Science 265, 2037-2048, 1994. Genetic variants associated with susceptibility to subsets of some common diseases such as breast cancer (BRCA-1 and -2), colon cancer (FAP and HNPCC), Alzheimer's disease (APP) and type II diabetes (MODY-1, -2, -3) have been identified by these methods, which has raised expectations. However, these genetic variants have a very strong effect in only a very limited subset of individuals suffering from these diseases (Risch, Nature, 405, 847-856, 2000).
Despite considerable effort, genetic variants accounting for susceptibility to common, non-Mendelian disorders in the general population have not been identified. Since multiple genetic loci are involved, and each individual locus makes a small contribution to overall disease susceptibility, it will be quite difficult to identify common disease susceptibility loci by applying conventional linkage and positional cloning methods to human populations. Mapping of disease susceptibility genes in human populations has also been hampered by variability in phenotype, genetic heterogeneity across populations, and uncontrolled environmental influences. The variable reports of linkage between the chromosome 1q42 region and systemic lupus erythematosus illustrate the difficulties encountered in human genetic studies. One group reported strong linkage between the 1q42 region (Tsao, J. Clin. Invest, 99, 725-731, 1997) and to microsatellite alleles of a gene (PARP) within that region (Tsao, J. Clin. Invest. 103, 1135-1140, 1999). In contrast, no evidence for association with the PARP microsatellite marker was noted (Criswell et al., J. Clin. Invest, June; 105, 1501-1502, 2000; Delrieu et al., Arthritis & Rheumatism 42, 2194-2197, 1999); and minimal (Mucenski, et al., Molecular & Cellular Biology 6, 4236-4243, 1986) or no linkage (Lindqvist, et al., Journal of Autoimmunity, March; 14, 169-178, 2000) to the 1q42 region was found in several other SLE populations analyzed. It is likely that additional tools and approaches will be needed to identify genetic factors underlying common human diseases.
Analysis of experimental murine genetic models of human disease biology should greatly facilitate identification of genetic susceptibility loci for common human diseases. Experimental murine models have the following advantages for genetic analysis: inbred (homozygous) parental strains are available, controlled breeding, common environment, controlled experimental intervention, and ready access to tissue. A large number of murine models of human disease biology have been described, and many have been available for a decade or more. Despite this, relatively limited progress has been made in identifying genetic susceptibility loci for complex disease using murine models. Genetic analysis of murine models requires generation, phenotypic screening and genotyping of a large number of intercross progeny. Using currently available tools, this is a laborious, expensive and time-consuming process that has greatly limited the rate at which genetic loci can be identified in mice, prior to confirmation in humans. For a review, see Nadeau and Frankel, Nature Genetics August; 25, 381-384, 2000.
The difficulties encountered in associating phenotypic variations, such as susceptibility to common diseases, with genetic variations gives rise to a need in the art for additional tools for identifying chromosomal regions that are most likely to contribute to quantitative traits or phenotypes. In view of this situation, it would be highly desirable to provide a technique for associating a phenotype with one or more candidate chromosomal regions in the genome of an organism without reliance on time consuming techniques such as cross breeding experiments or laborious post-PCR manipulation.